We propose to study the metabolism in vivo of malignant tissues using positron emission tomography (PET) and nuclear magnetic resonance (NMR) spectroscopy as complementary tools. We hypothesize these measurements will provide a sensitive method to assess the pathobiology of cancer and the mechanisms by which therapy kills or fails to kill tumors. Our measurements of biochemistry in vivo will provide insight into the metabolic consequences of disease processes as well as the differential sensitivity to treatment of tumors versus surrounding normal tissues. In this Program Project renewal a series of research projects will study relationships between blood flow, capillary permeability, energetics metabolism, and cellular proliferation in tumors and surrounding normal tissues. Since this program was first funded (May, 1986) we have gained considerable experience with PET and NMR procedures in our laboratory, using both animals and human patients as research subjects. The proposed studies will continue developing tracers of biologically important molecules, appropriate animal models for their validation, imaging physics for their accurate quantitation, and computerized mathematical analyses to interpret the metabolic images in terms of physiological and biochemical parameters. A major aspect of the basic research studies always involves validation of methods. The biomedical research projects follow a general sequence of questions about cellular function; Are cells receiving an adequate supply of nutrients? How much and by what pathways are they using these nutrients? Are the cells proliferating? Individual clinical projects will test specific hypotheses involving metabolic imaging for evaluating and/or following human disease. Specifically, these will include studies of tumors of the brain, lung, head and neck, breast, cervix, skin (melanoma), soft tissue sarcomas and osteosarcomas and lymphomas. The clinical problem of tumor resistance is largely the ability to identify its existence and, ideally, its cause in the individual patient. Pretreatment imaging and post-treatment imaging, correlated with patient clinical course, will lead to methods to predict by imaging alone how well a given tumor will respond to a given form of therapy. Metabolic imaging may also be used to select an alternate treatment that could work better and/or to determine whether healthy tissue surrounding tumor is being damaged too severly by a treatment. In summary, imaging of regional tumor metabolism, when supported by strong bench science to validate the interpretation of each imaging procedure, will eventually allow physicians to select optimal therapy for an individual patient and to critically evaluate therapy while it is in progress.